Highlights from Recent Cancer Literature
Journal: Cancer Research (2014)

Neurons rarely show malignant transformation in cancer, with embryonal tumor neuroblastoma, the third most common childhood cancer, representing a rare exception to this rule. Hackett and colleagues studied susceptibility in a genetically engineered mouse model of neuroblastoma. Combining genetics and gene-expression analyses in somatic tissues from mice of susceptible or resistant genetic backgrounds, they identified ARG1 (rate limiting for synthesis of the inhibitory neurotransmitter GABA) and GABA signaling as linked to susceptibility to neuroblastoma in mice. Expression of GABA genes was correlated with survival in human neuroblastoma, and activation of GABA or inhibition of ARG1 blocked growth of human neuroblastoma cells. These results implicate ARG1 and GABA in both neural development and neuroblastoma and suggest roles for benzodiazepines and other clinical GABA agonists in neuroblastoma.Hackett CS, Quigley DA, Wong RA, Chen J, Cheng C, Song YK, et al. Expression quantitative trait loci and receptor pharmacology implicate Arg1 and the GABA-A receptor as therapeutic targets in neuroblastoma. Cell Rep 2014;9:1–13.The dual-specificity EGFR/ERBB2 inhibitor lapatanib is employed primarily against advanced ERBB2-positive breast cancer. Lauriola and colleagues found—by happy accident—that omitting the commonly used supplement hydrocortisone from the culture medium of MCF-10A mammary epithelial cells accelerated cell migration. Glucocorticoids were found to suppress positive feedback loops and enforce negative feedback in EGFR signaling. For example, glucocorticoids induce DUSP1, a dual-specificity phosphatase that suppresses MAPK signaling. Glucocorticoid levels are under circadian control and peak at onset of the active period. The authors demonstrated circadian control of EGFR transcription, with high levels of glucocorticoids correlating with better prognosis in patients with breast cancer. Remarkably, drugs administered during the resting period in vivo showed enhanced efficacy in animals with EGFR-dependent tumors. These findings support a circadian clock–based paradigm in cancer therapy.Lauriola M, Enuka Y, Zeisel A, D'Uva G, Roth L, Sharon-Sevilla M, et al. Diurnal suppression of EGFR signalling by glucocorticoids and implications for tumour progression and treatment. Nat Commun 2014;5:5073.Casein kinase 1A1 (CSNK1A1) is a candidate gene for chromosome 5q deletion in myelodysplastic syndrome (MDS). Schneider and colleagues show that hematopoietic stem cells (HSC) heterozygous for Csnk1a1 had a competitive advantage in repopulating lethally irradiated bone marrow of mice. Heterozygous HSCs showed increased β-catenin activity, whereas Csnk1a1-null HSCs further activated β-catenin and decreased cellular viability. The differences in HSC outcome between the Csnk1a1-null and heterozygous HSCs likely resulted from enhanced activation of p53 in the null cells. Schneider and colleagues identified recurrent mutations in the retained allele of CSNK1A1 in MDS patients. HSCs heterozygous for CSNK1A1 showed increased sensitivity to inhibition. When reintroduced into HSCs homozygous null for Csnk1a1, such mutations increased β-catenin activity with less activation of p53 than homozyogusly deleted Csnk1a1. Importantly, such HSCs remained sensitive to CSNK1A inhibition, suggesting their potential in MDS therapy.Schneider RK, Ademà V, Heckl D1, Järås M, Mallo M, Lord AM, et al. Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS. Cancer Cell 2014;26:509–20.Colegio and colleagues explore tumor-derived signals that induce the M2-like polarization of tumor-promoting tumor-associated macrophages (TAM). Using carcinoma and melanoma cancer cell lines in syngeneic mice, they demonstrate that TAMs showed increased expression of Vegfa and Arg1, and that lactate in cell conditioned media could drive this phenotype in normoxic bone marrow–derived macrophages. Exposure of bone marrow–derived macrophages to lactate resulted in dose-dependent and HIF1α-dependent increases in Vegfa and Arg1 expression. Coinjection of tumor cells with lactate-stimulated versus control-stimulated bone marrow–derived macrophages conferred a growth advantage to the tumor. Interestingly, conditional ablation of macrophage Arg1 resulted in a marked reduction in carcinoma tumor growth. These studies emphasize the importance of tumor–macrophage communication in TAM polarization and identify a potential point of therapeutic intervention.Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, et al. Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature 2014;513:559-63.Unanswered questions remain regarding the origin of breast cancer stem cells and how they differ from normal mammary gland cells. Chakrabarti and colleagues, in a model of basal mammary epithelial cell biology, show that normal mammary stem cells in the basal compartment are maintained by the ΔNp63 transcription factor (an isoform of TRP63), a basal cell marker that in turn upregulates FZD7 and enhances Wnt signaling. Importantly, exactly the same pathway is activated in breast tumors in which ΔNp63 is overexpressed. Thus, similar pathways are activated in normal and cancer stem cells. Interestingly, the ΔNp63 pathway can drive breast cancers without activating mutations in the Wnt pathway. While this pathway may be targetable in breast cancer, how such targeting would affect normal mammary glands remains uncertain.Chakrabarti R, Wei Y, Hwang J, Hang X, Andres Blanco M, Choudhury A, et al. ΔNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling. Nat Cell Biol 2014;16:1004–15.Emdad and colleagues link a tumor suppressor microRNA (miR-184) and a cancer-promoting gene, SND1, in glioma. Forced expression of miR-184 decreased proliferation and invasion of glioma cells through direct regulation of SND1. High SND1 mRNA and protein were evident in human glioma tissue. Patients with intermediate levels of SND1 survived longer than patients showing elevated SND1 expression. Overexpression of SND1 in human astrocytes enhanced invasion and colony formation, whereas knockdown of SND1 in glioma cells decreased them. In intracranial human glioma xenografts, the SND1 knockdown and miR-184 overexpression groups showed improved survival associated with decreased proliferation and angiogenesis, activated STAT3, and enhanced apoptosis. This new understanding of relationships between miR-184 and SND1 may lead to development of drugs that reduce SND1 expression and improve outcomes.Emdad L, Janjic A, Alzubi MA, Hu B, Santhekadur PK, Menezes ME, et al. Suppression of miR-184 in malignant gliomas upregulates SND1 and promotes tumor aggressiveness. Neuro Oncol 2014 Sep 12. [Epub ahead of print].Note: Breaking Advances are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.